Discovery of PiragliatinFirst Glucokinase Activator Studied in Type 2 Diabetic Patients

Glucokinase (GK) activation as a potential strategy to
treat type
2 diabetes (T2D) is well recognized. Compound 1, a glucokinase
activator (GKA) lead that we have previously disclosed, caused reversible
hepatic lipidosis in repeat-dose toxicology studies. We hypothesized
that the hepatic lipidosis was due to the structure-based toxicity
and later established that it was due to the formation of a thiourea
metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification
studies, followed by the independent synthesis and profiling of the
cyclopentyl keto- and hydroxyl- metabolites of 3, led
to the selection of piragliatin, 4, as the clinical lead.
Piragliatin was found to lower pre- and postprandial glucose levels,
improve the insulin secretory profile, increase β-cell sensitivity
to glucose, and decrease hepatic glucose output in patients with T2D.